Prostate cancer is the second leading cause of cancer-related death among men in the United States. Receptor tyrosine kinases are emerging as potential therapeutic targets in prostate cancer, as inhibition of receptor tyrosine kinases have been shown to reduce prostate tumor growth both in vivo and in vitro. This data therefore suggests that receptor tyrosine kinases may play an important role in prostate cancer and should be considered in the development of novel therapeutics. One such receptor, the Ron receptor tyrosine kinase, has been shown by our laboratory to be overexpressed in human prostate cancer and that its expression is highest in metastatic tissues. In addition, we have also demonstrated that the Ron receptor positively regulates angiogenic chemokine production in an NF-kB-dependent manner in epithelial prostate cancer cell lines. Our preliminary data also show that Ron expression is significantly increased during the development of prostate cancer in mice in the TRAMP model and that loss of Ron in TRAMP mice leads to a decrease in prostate tumor mass, vascularization and NF-kB activation. However, despite this, the precise role that Ron plays in the prostate epithelium in this model is unknown. Macrophages have also been shown to play an important role in tumor initiation, progression and metastasis by either promoting or inhibiting tumor growth. We and others have shown that Ron expression on several macrophage populations is important in the regulation of macrophage responses such as tissue repair and macrophage polarization, which have also been shown to be important in the maintenance of a tumor microenvironment. Our preliminary data suggests that Ron signaling in myeloid cells (macrophages and granulocytes) is crucial to maintaining a pro-tumorigenic microenvironment and consequently, to tumor establishment in an orthotopic model of prostate cancer. However, the specific contributions of Ron signaling in macrophages to tumor initiation, growth, progression and metastasis in a single model have not been evaluated. We therefore hypothesize that Ron receptor tyrosine kinase signaling in the prostate epithelium and in myeloid cells promotes prostate tumorigenesis via interdependent mechanisms. The studies in this proposal have the potential to define the importance of Ron signaling in macrophage/myeloid cells and in the tumor cells in promoting tumor growth and may suggest a paradigm shift in our thinking about this receptor as a tumor promoter, as well as suggest novel avenues for the development of targeted therapeutics.